Gastrointestinal · PANCE / PANRE

Colorectal Cancer (CRC)

Adenocarcinoma arising from adenomatous or sessile serrated polyps; preventable with screening.

Also known as: colon cancer, rectal cancer, colorectal cancer, CRC

Overview

Malignant neoplasm of the colon or rectum, predominantly adenocarcinoma arising from adenomatous (tubular, tubulovillous, villous) or sessile serrated polyps. Anatomic and biologic differences between right colon, left colon, and rectum influence presentation, treatment, and prognosis.

Epidemiology

Second leading cause of cancer death in the US (~150,000 new cases, ~52,000 deaths annually). 5-year survival ~65% (>90% if localized, ~15% if metastatic). Lifetime risk ~4%. Incidence falling overall due to screening, but rising in adults <50 (early-onset CRC).

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Risk factors

Age — median diagnosis ~67 (but rising in younger adults)
Personal or family history of CRC or adenomatous polyps
Inherited syndromes: Lynch syndrome (HNPCC, MMR mutation), familial adenomatous polyposis (FAP, APC), MUTYH-associated polyposis, Peutz-Jeghers, juvenile polyposis
Inflammatory bowel disease (UC > Crohn colitis); risk ~8-10 yr after diagnosis with extensive colitis
Primary sclerosing cholangitis (synergistic with IBD)
Diet: high red/processed meat, low fiber, low fruits/vegetables
Smoking, heavy alcohol
Obesity, type 2 diabetes, sedentary lifestyle
African American ethnicity (higher incidence and mortality)
Prior abdominal radiation

Pathophysiology

Adenoma-carcinoma sequence: normal mucosa → adenoma (APC loss) → carcinoma (KRAS, SMAD4/DPC4, TP53 mutations), taking ~10 years. Alternate serrated pathway: BRAF mutation → CpG island methylator phenotype (CIMP) → sessile serrated lesion → carcinoma. Lynch syndrome: germline mismatch repair (MLH1, MSH2, MSH6, PMS2, EPCAM) defects → microsatellite instability (MSI-H).

Clinical presentation

Symptoms

Right-sided (cecum/ascending): occult bleeding → iron-deficiency anemia, fatigue, weight loss; large lumen tolerates mass before obstruction
Left-sided (descending/sigmoid): change in stool caliber (narrow/pencil-thin), constipation alternating with diarrhea, hematochezia, obstruction earlier (narrower lumen)
Rectal: hematochezia, tenesmus, rectal pain, change in bowel habit
Systemic: weight loss, fatigue, anorexia
Metastatic: hepatomegaly, jaundice, ascites, bone pain, cough

Signs / physical exam

Pallor (anemia)
Palpable abdominal mass
Hepatomegaly if liver metastases
Rectal mass on DRE (most rectal cancers within reach)
Lymphadenopathy (Virchow node — rare)
Streptococcus gallolyticus (bovis) bacteremia or endocarditis — colonoscopy mandatory

Classic findings

Older adult with iron-deficiency anemia of unclear source (right colon), or change in bowel habit with rectal bleeding (left colon/rectum).

Differential diagnosis

Diverticulitis or diverticular disease — LLQ pain, fever; CT distinguishes; colonoscopy 6-8 wk later to exclude CRC
Inflammatory bowel disease — Younger patient, chronic bloody diarrhea, extraintestinal manifestations
Hemorrhoids / anal fissure — Bright red blood on toilet paper; never assume in older adult without colonoscopy
Ischemic colitis — Sudden bloody diarrhea, watershed areas
Infectious colitis — Acute onset, exposure, positive stool studies
Other GI malignancies (small bowel, anal) — Imaging and biopsy
Endometriosis (rectal) — Cyclic rectal bleeding in young women

Diagnostic workup

Diagnostic criteria

Histologic confirmation by colonoscopic biopsy. Staging by AJCC 8th edition TNM. Screening modalities (USPSTF: average-risk adults 45-75): colonoscopy every 10 yr, FIT annually, FIT-DNA (Cologuard) every 3 yr, flexible sigmoidoscopy every 5-10 yr ± FIT annually, CT colonography every 5 yr.

Labs

CBC (microcytic anemia)
BMP, LFTs (liver metastases)
CEA — baseline at diagnosis; surveillance marker (not for screening)
Iron studies

Imaging

Colonoscopy with biopsy — DIAGNOSTIC; tattoo lesion for surgical localization
CT chest/abdomen/pelvis with contrast — staging (M assessment)
Rectal cancer: pelvic MRI (T and N staging), endorectal ultrasound (early T staging)
PET-CT not routine; selected cases for equivocal metastases
Mismatch repair (MMR) or MSI testing on all CRCs — Lynch syndrome screening and immunotherapy candidacy
KRAS, NRAS, BRAF, HER2 testing for metastatic disease to guide therapy

Diagnostic algorithm

Feature	Right-sided CRC	Left-sided CRC	Rectal Cancer
Typical presentation	Iron-deficiency anemia, occult bleeding, weight loss	Change in stool caliber, hematochezia, obstruction	Hematochezia, tenesmus, change in bowel habit
Lumen size	Wide (late obstruction)	Narrower (earlier obstruction)	Narrow
Molecular features	More MSI-H, BRAF V600E, CIMP	More chromosomal instability, KRAS	Similar to left colon
Response to anti-EGFR	Poor	Good if RAS/RAF wild-type	Variable
Staging imaging	CT chest/abd/pelvis	CT chest/abd/pelvis	Pelvic MRI required
Prognosis (stage-matched)	Worse for advanced	Better	Local recurrence higher; need TME

Anatomic location influences CRC presentation, molecular biology, treatment response, and prognosis.

Treatment

First-line

Multidisciplinary team approach
Stage-directed therapy (see by_subtype)
Curative-intent surgery is the cornerstone for non-metastatic disease
Lifestyle and risk factor counseling

Stage 0 (Tis) / Stage I (T1-T2 N0)

Polyp with carcinoma in situ or T1: endoscopic resection with clear margins may suffice if low-risk features
Surgical resection (segmental colectomy or low anterior resection / APR for rectum) for higher-risk lesions
No adjuvant chemotherapy

Stage II (T3-T4 N0)

Surgical resection with adequate lymphadenectomy (≥12 nodes)
Adjuvant chemotherapy (5-FU-based ± oxaliplatin — FOLFOX) for high-risk Stage II (T4, perforation, obstruction, <12 nodes harvested, poorly differentiated, lymphovascular invasion, MSI-stable)
MSI-H Stage II patients generally do NOT benefit from 5-FU monotherapy

Stage III (any T, N+)

Surgical resection
Adjuvant FOLFOX or CAPOX × 3-6 months
IDEA trial: 3 months may be sufficient for low-risk Stage III (T1-3, N1)

Locally advanced rectal cancer (T3-T4 or N+)

Total neoadjuvant therapy (TNT) — induction chemo + chemoradiation OR chemoradiation + consolidation chemo, followed by total mesorectal excision (PRODIGE 23, RAPIDO)
Watch-and-wait approach for complete clinical responders (selective)

Stage IV (metastatic)

Systemic therapy: FOLFOX, FOLFIRI, FOLFOXIRI ± bevacizumab (anti-VEGF) or anti-EGFR (cetuximab, panitumumab — only for RAS/RAF wild-type left-sided tumors)
Targeted therapy by molecular profile: encorafenib + cetuximab for BRAF V600E; trastuzumab-based for HER2+; pembrolizumab/nivolumab for MSI-H/dMMR
Metastasectomy (liver, lung) for oligometastatic disease — potentially curative
Palliative resection/diversion/stent for obstructing tumors

Complications

Bowel obstruction or perforation
Fistula formation
Anemia, hemorrhage
Metastases — liver (most common), lung, peritoneum, ovary (Krukenberg, although gastric more classic), bone, brain
Recurrence after curative resection (~30%)
Treatment toxicity: oxaliplatin neuropathy, irinotecan diarrhea, 5-FU mucositis, anti-EGFR rash

PANCE pearls

USPSTF lowered CRC screening start age to 45 in 2021 due to rising early-onset disease.
Iron-deficiency anemia in postmenopausal women and any man requires evaluation for GI bleeding — colonoscopy + EGD.
Streptococcus gallolyticus (S. bovis) bacteremia or endocarditis — colonoscopy is mandatory to exclude colon cancer.
Universal MMR/MSI testing on all CRCs at diagnosis identifies Lynch syndrome AND immunotherapy candidates.
MSI-H/dMMR metastatic CRC responds dramatically to pembrolizumab (KEYNOTE-177).
Anti-EGFR therapy (cetuximab, panitumumab) requires RAS/RAF wild-type AND is most effective in LEFT-sided primaries.
Bevacizumab — contraindicated for 28 days post-surgery (poor wound healing, perforation risk).
Rectal cancer requires pelvic MRI for staging (T and N) — drives neoadjuvant therapy decisions.
Surveillance after curative resection: CEA every 3-6 mo × 5 yr, CT chest/abdomen/pelvis annually × 5 yr, colonoscopy at 1 yr then every 3-5 yr.
Lynch syndrome: start colonoscopy at age 20-25 every 1-2 yr; consider screening for endometrial, ovarian, gastric, urothelial cancers.

References

USPSTF 2021 — US Preventive Services Task Force. Screening for Colorectal Cancer. JAMA 2021;325:1965-1977
NCCN 2024 — NCCN Guidelines Version 5.2024 — Colon Cancer; Rectal Cancer
ACG 2021 — Shaukat A et al. ACG Clinical Guidelines: Colorectal Cancer Screening 2021. Am J Gastroenterol 2021;116:458-479
KEYNOTE-177 — André T et al. Pembrolizumab in MSI-H–Deficient Mismatch Repair Metastatic Colorectal Cancer. NEJM 2020;383:2207-2218

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